In a wide variety of circumstances, animals, including humans, can suffer from bleeding due to wounds or during surgical procedures. In some circumstances, the bleeding is relatively minor, and normal blood clotting functions in addition to the application of simple first aid are all that is required. In other circumstances, substantial bleeding can occur. These situations usually require specialized equipment and materials as well as personnel trained to administer appropriate aid.
Bleeding during surgical procedures may manifest in many forms. It can be discrete or diffuse from a large surface area. It can be from large or small vessels, arterial (high pressure) or venous (low pressure) of high or low volume. It may be easily accessible or it may originate from difficult to access sites. The control of bleeding is essential and critical in surgical procedures to minimize blood loss, to reduce post-surgical complications, and to shorten the duration of the surgery in the operating room. The selection of appropriate methods or products for the control of bleeding is dependent upon many factors, which include but are not limited to bleeding severity, anatomical location of the source and the proximity of adjacent critical structures, whether the bleeding is from a discrete source or from a broader surface area, visibility and precise identification of the source and access to the source.
Conventional methods to achieve hemostasis include use of surgical techniques, sutures, ligatures or clips, and energy-based coagulation or cauterization. When these conventional measures are ineffective or impractical, adjunctive hemostasis techniques and products are typically utilized.
To address the above-described problems, materials have been developed for controlling excessive bleeding or as adjuncts to hemostasis. Topical Absorbable Hemostats (TAHs) are widely used in surgical applications. TAHs encompass products in various forms, such as based on woven or non-woven fabrics or sponges, and are typically made of at least partially resorbable materials, ranging from natural to synthetic polymers and combinations thereof, including lactide-glycolide based co-polymers such as polyglactin 910, oxidized cellulose, oxidized regenerated cellulose (ORC), gelatin, collagen, chitin, chitosan, starch etc. Gelatin is used in various forms with or without a topical thrombin solution. Also, widely used are biologically active topical hemostatic products (topical thrombin solutions, fibrin sealants, etc.) and a variety of synthetic topical sealants.
To improve the hemostatic performance, scaffolds based on the above mentioned TAH materials can be combined with biologically-derived clotting factors, such as thrombin and fibrinogen.
Due to its biodegradability and its bactericidal and hemostatic properties, oxidized cellulose, as well as oxidized regenerated cellulose has long been used as a topical hemostatic wound dressing in a variety of surgical procedures, including neurosurgery, abdominal surgery, cardiovascular surgery, thoracic surgery, head and neck surgery, pelvic surgery and skin and subcutaneous tissue procedures. Many methods for forming various types of hemostats based on oxidized cellulose materials are known, whether made in powder, woven, non-woven, knit, and other forms. Currently utilized hemostatic wound dressings include knitted or non-woven fabrics comprising oxidized regenerated cellulose (ORC), which is oxidized cellulose with increased homogeneity of the cellulose fiber.
Fibrinogen and thrombin are critical proteins involved in achieving hemostasis after vascular injury and essential to blood clot formation. Fibrinogen and thrombin can be combined in powder form or in a non-aqueous suspension, without initiating a typical clotting reaction, thus preventing the formation of a fibrin clot until the proteins are hydrated in an aqueous medium or other liquid environment in which the proteins are soluble. An admixture of these proteins in powder form have a variety of potential biomedical applications including topical hemostasis, tissue repair, drug delivery, etc. In addition, an admixture of these proteins may be loaded onto a carrier or substrate, or other medical device, in powder form to form a product that may be used for example as a hemostatic device.
Fibrin sealants, also known as fibrin glue, have been in use in the clinic for decades. Oftentimes, fibrin sealant consists of two liquid components, a fibrinogen comprising component and a thrombin comprising component, which are stored frozen due to their inherent instability. Sometimes fibrin sealant products consist of two freeze dried components, which require reconstitution immediately prior to use and delivery by a conjoined syringe or other double-barreled delivery device. Freeze dried formulations are typically stable, but the fibrinogen component is difficult to reconstitute. Many hemostatic formulations currently available on the market or in development utilize lyophilized fibrinogen, frequently in combination with lyophilized thrombin, with hemostatic formulations applied in the form of dry powder, semi-liquid paste, liquid formulation, or optionally disposed on a supporting scaffold such as absorbable fabric scaffold.
To provide dressings with enhanced hemostatic and tissue sealing and adhering properties, therapeutic agents, including, but not limited to, thrombin, fibrin and fibrinogen have been combined with dressing carriers or substrates, including gelatin-based carriers, polysaccharide-based carriers, glycolic acid or lactic acid-based carriers and a collagen matrix.
U.S. Pat. No. 8,858,969, entitled Hemostatic compositions, devices, and methods, discloses a hemostatic device comprising: a container comprising a bottle, vial, canister, tube, or reservoir with an interior enclosure which contains a flowable hemostatic composition comprising a clay dispersed in an aqueous medium; wherein at least about 50% of the clay comprises particles with a particle size between about 1 nm and 10 μm; wherein the composition is a liquid which is substantially free of visible clay particles such that an appreciable amount of the clay particles does not settle from the liquid upon standing for at least about 12 hours; and wherein the composition is sterilized; and a dispensing component in fluid communication with the container; wherein the device is configured so that the dispensing component is capable of dispensing the hemostatic composition from the container directly to a bleeding area of an animal or person.
U.S. Patent Publication No. 2014/0369991, entitled Formulations for Wound Therapy discloses a pharmaceutical composition comprising an absorbable carrier of a biocompatible, biodegradable polymer and dispersed, at least partially through or on said absorbable carrier, microparticles comprising fibrinogen in an amount of from about 0.1-15 mg/cm2 and/or microparticles comprising thrombin in an amount of from about 0.01 to 500 IU/cm2, wherein the microparticles further comprise a glassy carrier.
U.S. Patent Publication No. 2016/0206773, entitled Composition and Method for Stopping Hemorrhage, Infection, and Accelerating Healing in Various Types of Wound or Burns discloses a composition, comprising: a hydrogel matrix comprising at least one polymer cross linked, via ionic or covalent bonding, with both hyaluronic acid and alginic acid, wherein the at least one polymer is selected from the group consisting of chitosan, poly L-Lysine, or a combination thereof.
U.S. Pat. No. 9,265,858, entitled Dry haemostatic composition discloses a method of preparing a dry composition suitable for use in haemostasis and wound healing, comprising the sequential steps of: a) providing a cross-linked biocompatible polymer in powder form, one or more polyols and an aqueous medium, wherein the one or more polyols are selected from sugar alcohols and sugars; b) mixing the biocompatible polymer, the one or more polyols and the aqueous medium to obtain a paste; and c) freeze-drying the paste to produce a dry composition, wherein the dry composition is capable of reconstituting to form a substantially homogeneous paste without mechanical mixing, wherein the dry composition comprises from 10% w/w to 60% w/w of one or more polyols.
U.S. Pat. No. 2,772,999, entitled Hemostatic surgical compositions and dressings discloses a surgical composition for coagulating blood containing a hemostatic amount, at least about 2%, of cellulose derivative of the group consisting of free acid cellulose glycolic acid ether and free acid cellulose hydroxypropionic acid ether having degree of substitution at least about 0.5, and degree of neutralization in the approximate range 0 to 60% but sufficiently low so that the free carboxyl content of the cellulose is at least 0.5 per glucose unit.
U.S. Patent Publication No. 2004/0101548, entitled Hemostatic wound dressing containing aldehyde-modified polysaccharide discloses a hemostatic wound dressing, comprising: a substrate for contacting a wound, said substrate comprising; a wound-contacting surface; and a biocompatible, aldehyde-modified polysaccharide, wherein said wound dressing is hemostatic.
European Publication No. EP1493451, entitled Hemostatic devices and methods of making same discloses a composition, comprising: biocompatible, oxidized cellulose particles having an average designated nominal particle size of from about 0.035 to about 4.35 mm; and a biocompatible, porous water-soluble or water-swellable polysaccharide binder component; wherein said composition is suitable for use in a hemostatic device.
U.S. Pat. No. 3,328,259, entitled Dressing for a wound containing a hemostatic agent and method of treating a wound discloses a dressing for a wound comprising a flexible body large enough to cover an open lesion as a dressing, said 40 body containing a water-soluble plasma-soluble cellulose derivative having hemostatic and film-forming properties and having the property of combining with the plasma in a wound to form with said plasma an artificial water-insoluble eschar, said cellulose derivative being present in integral non-discrete form in said body and in proportions to cause said body to be effective in coagulating the plasma issuing from a moist lesion to which the dressing is applied.
U.S. Patent Publication No. 2007/0207180, entitled Synthetic polypeptide-containing bioapplicable material and film-forming material discloses a bioapplicable material containing a polypeptide, wherein the polypeptide comprises a synthetic polypeptide having at least an amino acid sequence represented by the formula: Pro-Y-Gly, wherein Y represents Pro or Hyp, and forming a collagen-like structure.
U.S. Patent Publication No. 2012/0070470, entitled Hemostatic compositions, devices, and methods, discloses a blood-clotting agent comprising: a composition comprising clay dispersed in a liquid medium, wherein the clay is less than about 10% by weight of the composition; and wherein the composition including the liquid medium and clay has a viscosity of about 1000 cP or less.
U.S. Patent Publication No. 2002/0197302, entitled Hemostatic polymer useful for rapid blood coagulation and hemostasis discloses a method for arresting bleeding and inducing rapid blood coagulation and clot formation at a bleeding site, comprising applying a dry dressing comprising a matrix containing a hemostasis-promoting amount of a hemostatic agent which accelerates blood coagulation and clot formation at an interface between a wound surface and hemostatic zone to said bleeding site for a period of time sufficient to induce rapid blood coagulation at said site and removing the dressing after the blood at said bleeding site has clotted.
U.S. Patent Publication No. 2005/0226916, entitled Hemostatic polymer useful for Rapid blood coagulation and hemostasis discloses a method for promoting blood coagulation at a bleeding site in a mammal comprising applying to said bleeding site a composition comprising porous polymeric spheres and allowing said blood coagulation to occur at said bleeding site.
Chinese Patent Publication No. CN101001649A, entitled Haemostatic composition comprising hyaluronic acid discloses hemostatic composition, comprising a bioabsorbable material and hyaluronic acid (HA) or a derivative thereof.
U.S. Pat. No. 4,002,173, entitled A Diester crosslinked polyglucan hydrogels and reticulated sponges thereof relates to hydrogel compositions of diester crosslinked polyglucans and a process for their preparation.
Chinese Patent Application Publication No. CN102379827A Toothpaste containing dencichine and preparation method thereof relates to a toothpaste that has CMC is one of its components.
U.S. Patent Publication No. 2005/0037088, entitled Process of making flowable hemostatic compositions and devices containing such compositions discloses a process for making a flowable hemostatic composition, comprising: introducing a volume of a biocompatible liquid into a mixing vessel equipped with a means for mixing said liquid, introducing a volume of a biocompatible gas into said volume of liquid while said means for mixing is operating under conditions effective to mix said liquid and said gas together to form a foam comprising a discontinuous gas phase comprising said gas substantially homogenously dispersed throughout a continuous liquid phase comprising said liquid, introducing into said foam an amount of solid particles of a biocompatible polymer suitable for use in hemostasis and which is substantially insoluble in said liquid; and mixing said foam and said solid particles together under conditions effective to form a substantially homogenous composition comprising said discontinuous gas phase and said particles substantially homogenously dispersed throughout said continuous liquid phase, wherein the ratio of said volume of liquid, said volume of gas and said amount of solid particles is effective to provide said substantially homogeneous composition with hemostatic properties, thereby forming said flowable hemostatic composition.
U.S. Patent Publication No. 2005/0284809, entitled Hemostatic compositions and devices, discloses a plurality of packed particles comprising interstitial pores having a pore volume and a median pore diameter effective to provide improved absorption of physiological fluids or an aqueous media into said interstitial pores when placed in contact therewith, compared to a plurality of unpacked particles of the same material, said particles comprising a biocompatible material and having a median diameter suitable for use in providing hemostasis to a site of a body of a mammal requiring hemostasis.
U.S. Pat. No. 7,083,806, entitled Wound gels, discloses a hydrogel comprising a pre-crosslinked gellant, water, and a poloxamer, wherein the concentration of said poloxamer is between 10 and 25% by weight of the hydrogel and the gellant comprises at least one cross-linked, superabsorbent polysaccharide, said hydrogel exhibiting thermally induced viscosification at a temperature between ambient and 35° C., and wherein said hydrogel has the capacity to absorb at least 50% further water in addition to the water already present, specifying water presence in the hydrogel.
European Publication No. 1942117A1, entitled Derivatives of acid polysaccharides discloses acid polysaccharides characterized by the concomitant presence of partial esters with non-polysaccharide carboxylic acids and esters between the acid groups of the initial polysaccharide and the alcohol groups of the repetitive units, with the formation of crosslinking between the polysaccharide chains.
U.S. Pat. No. 9,353,191, entitled Method for producing hydrogels, discloses a polymer hydrogel consisting essentially of carboxymethyl cellulose cross-linked with citric acid characterized by (a) a tapped density of at least 0.5 g/cm3; and (b) a media uptake ratio in simulated gastric fluid/water (1:8) of at least about 50 at 37° C.
U.S. Pat. No. 8,658,147B2, Polymer hydrogels and methods of preparation thereof (also European Patent Publication No. EP2532685A1) discloses a method of treating obesity in a subject in need thereof, comprising the step of orally administering to the subject a therapeutically effective amount of a polymer hydrogel comprising carboxymethyl cellulose covalently cross-linked with citric acid.
U.S. Pat. No. 5,905,092, entitled Topical antibiotic composition providing optimal moisture environment for rapid wound healing that reduces skin contraction discloses a composition for the treatment of wounds comprising: a topical semisolid which is capable of providing a moist environment for a wound by promoting increased water content in wounds becoming dry and promoting reduced water content in wounds having excess exudate, comprising vehicles, which are capable of incorporating water to at least about 30% of their initial application weight, while also being capable of retaining at least about 70% of their application weight for two hours when left on a non-absorbing surface; an antibiotic formulation; and at least 60% by weight of water, wherein the topical semisolid comprises from about 10% to about 20% by weight of a polyhydric alcohol and from about 0.5% to about 10% by weight each of two or more gelling agents selected from the group consisting of hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, cross-linked acrylic acid polymer, PVM/MA decadiene crosspolymer and ammonium acrylates/acrylonitrogen.
U.S. Patent Publication No. 2013/0108682, entitled Wound Care Product Comprising a Cathelicidin Polypeptide, discloses a wound care product comprising a wound care material and a polypeptide having wound healing properties, wherein the polypeptide having wound healing properties is a cathelicidin, or a fragment, variant or fusion thereof which retains, at least in part, the wound healing activity of said cathelicidin.
U.S. Pat. No. 8,829,053, entitled Biocidal compositions and methods of using the same discloses an antimicrobial composition, comprising: at least one polymeric biguanide in an amount of at least 0.05 weight %, a chelating agent at a concentration of from 0.01 weight % to 1 weight %, and a vicinal diol component comprising at least one monoalkyl glycol and at least one monoalkyl glycerol, wherein a weight ratio of said at least one polymeric biguanide and said vicinal diol component ranges from 1:0.05 to 1:500, wherein said antimicrobial composition kills at least 99.99% of organisms in a biofilm within ten minutes of treatment with said antimicrobial composition.
U.S. Patent Publication No. 2014/0105950, entitled Haemostatic Material discloses a haemostatic material comprising a haemostat agent and a bioadhesive agent, wherein the haemostat agent is selected from the list consisting of: oxidised regenerated cellulose, kaolin, gelatin, calcium ions, zeolite, collagen, chitosan and chitosan derivatives.
An article “Novel Superabsorbent Cellulose-Based Hydrogels Crosslinked with Citric Acid” by Christian Demitri, et al., Journal of Applied Polymer Science, Vol. 110, 2453-2460 (2008) discloses the preparation of new environmentally friendly hydrogels derived from cellulose and hence originating from renewable resources and characterized by biodegradable properties. Two cellulose derivatives, sodium carboxymethyl cellulose (CMCNa) and hydroxyethyl cellulose (HEC), were used for superabsorbent hydrogel preparation. Citric acid (CA), a crosslinking agent able to overcome toxicity and costs associated with other crosslinking reagents, was selected in a heat activated reaction. Differential scanning calorimeter (DSC), Fourier transform infrared spectroscopy (FTIR), and swelling measurements were performed during the reaction progress to investigate the CA reactivity with each of the polymers. Also, CMCNa/HEC polymer mixtures (3/1 w/w) crosslinked with CA were investigated and compared with previous results.
There is a need in improved hemostatic forms and materials which facilitate ease of application and rapid onset of hemostasis.